Neomycin salt of higher fatty acids



3 013 007 NEQMYCEQ SALT 6F IillGHER FATTY AClDS Hack K. Dale, Kalamazoo,Mich, assignor to The Upjohn Company, Kalamazoo, Mich, a corporation ofDelaware No Drawing. Filed Aug. 8, 1954 Ser. No. 47,916 17 Claims. (Cl.26il-2l0) This invention relates to salts of the antibiotic neomycin andmore particularly to neomycin higher fatty acid salts and neomycin saltsof mixed higher fatty acids.

The present invention is a continuation-in-part of application SerialNo. 587,462, filed May 28, 1956.

The present invention provides as novel and useful compositions ofmatter neomycin higher fatty acid salts and neomycin salts of mixedhigher fatty acids, wherein the fatty acids contain from 12 to 18 carbonatoms, inclusive.

It has been found that neomycin in either the free base or salt formcombines with the said fatty acids and mixed fatty acids to form novelcompounds which possess germicidal detergent activity per se and whichcan be combined with soap and synthetic organic detergents to provideadvantageous germicidal detergent combinations. The said compounds andcombinations possess germicidal detergent activity generally and areespecially advantageous for 'the reduction of both transient andresident bacteria upon human skin.

As used in the specification and claims of this application, the termneomycin has reference to the antibiotics more fully described inWaksman, Neomycin, The Williams and Wilkins Company, Baltimore,Maryland, 1958. The term includes the separate closely relatedantibiotics known as neomycin B and neomycin C and the mixtures thereof.

The neomycin reactant can be in the form of the free base or the salts,such as the sulfate and hydrochloride. The fatty acid reactant can be inthe form of the free fatty acids, the alkali-metal salts of the acids,the alkali-metal soaps, oil soaps, tallow soaps, and the like.

For complete reaction six molar equivalents of'the fatty acid or mixedfatty acids are theoretically required to react With the neomycin.However, an excess of the fatty acid is preferably used to obtainoptimum yields.

The compounds can be made using a lower alkanol as the solvent for thefatty acid, and an aqueous solution of the neomycin. The reaction canalso be accomplished in aqueous solutions of the alkali-metal salts ofthe fatty acids. Such solutions can take the form of aqueous solutionsof soap, for example, 'tallow and coconut oil soaps. Tallow from 'beefcontains relatively larger percentages of palmitic acid (C stearic acid(C and oleic acid (C and lesser percentages of lauric'acid (C myristicacid (C 4), palmitoleic acid (C and arachidic acid (C Goat and muttontallow also contain relatively larger percentages of the palmitic,stearic, and oleic acids.

It is preferred to use hydrogenated 'tallow. Coconut oil soap containsrelatively larger percentages of lauric acid (C and myristic acid (C andlesser percentages of the other higher fatty acids. The neomycin fattyacid compounds can also be prepared, for example, by mixing loweralkanol solutions of neomycin base and of the fatty acid, evapora ingoif the solvent and recovering the solid derivative. Another methodcomprises mixing an aqueous solution of neomycin acid addition salt andan alkali-metal salt of the fatty acid, recovering the insoluble productand purifying, for example, by washing out soluble by-products such assodium sulfate, and drying.

The following examples set forth the best mode contemplated by theinventor of carrying out his invention but are not to be construed aslimiting.

Example 1.-S0ap solution of neomycin salt of coconut oil fatty acids Toan aqueous solution of 40% coconut oil soap was added 0.1% neomycin baseas a cold solution. A precipitate was formed which became clear in lessthan one minute. The same result was obtained using 0.143% neomycinsulfate; the precipitate which formed became clear after fifteenminutes.

Example 2.Ne0mycin higher fatty acid salts Thirty grams of crudeneomycin sulfate is dissolved in '90 mls. of distilled water, and thenmixed with 9.6 gms. of activated carbon for fifteen minutes followed byfiltration and washing of the residue with 25 mls. of distilled Water.This preliminary step can be eliminated if pure neomycin sulfate isbeing used.

The neomycin sulfate filtrate solution .is then mixed with 300 mls. ofbarium hydroxide solution (31.55 gms. of Ea(OH) -5H O diluted to 360mls. with deaerated distilled water) to give a pH of 11.95. Theresulting barium sulfate precipitate is removed by filtration and theclear solution is titrated with 22 mls. of one half normal sulfuric acidto precipitate .excess barium ion. Filtering again, followed by washingthe filter with water yielded purified neomycin base which was dilutedwith water to 450 mls.

To 30 mls. of this purified neomycin base solution there was added 0.01equivalents of fatty acid, specifically lauric acid, stearic acid, orpalmitic acid dissolved in absolute methanol. The mixture was thenvacuum dried to give neomycin laurate, neomycin stearate, or neomycinpalmitate.

Example 3. Ne0mycin stearate A dispersion of 306 gms. of sodium'stearate in '6 l. of distilled water at 70 C. was mixed and stirredwith a solution of 200 gms. of neomycin sulfate in 600 mls. of distilledwater. The white waxy precipitate was separated by filtration and washedwith water to yield 340 gms. of neomycin stearate. This neomycinstearate in fine powdered form is suitable as an antiseptic dustingpowder possessing detergent properties. Without additional milling, itis incorporated in a soap crutching-operation, as are the other neomycinhigher fatty acid salts of Example 2 to produce germicidal soaps.

Alternatively, the neomycin compound can be incorporated in shavingcream to prepare a cream possessing advantageous effects in combattinginfections resulting from cuts during shaving.

Example 4.Neomycin 'laurate Laurie .acid

evaporated to dryness.

The dried neomycin laurate is powdered in a mortar.

Example 5.Neomycin myristate Myristic acid gms 2.28 Neomycin base gms1.4 Ethanol mls A solution of the myristic acid is prepared in 100 mls.of ethanol and the neomycin is added thereto. The re sulting mixture isevaporated to dryness in a vacuum desiccator to obtain dried neomycinmyristate. The yield is 2.9 gms.

Example 7.-Nemycin myristate A dispersion of 275 gms. of sodiummyristate in 6 l. of distilled water at 70 C. is mixed and stirred witha solution of 150 gms. of neomycin sulfate in 600 mls. of distilledwater. The white waxy precipitate is separated by filtration and washedwith water to yield 300 gms. of neomycin myristate. This product in finepowder form is suitable as an antiseptic dusting powder. Alternatively,it can be incorporated into bar soap at the time of milling the soapchips.

Example 8.--Ne0mycin salt of coconut oil fatty acids To 4400 mls. ofaqueous potash coconut oil soap is added 103 gms. of neomycin base as acold 10% aqueous solution. The pH is adjusted to 8 with dilute sulfuricacid. The precipitate is recovered, washed with water and dried in avacuum desiccator. 210 gms. of the neomycin salt of the mixed higherfatty acids are obtained. This neomycin salt can be dissolved in excesssoap to provide a liquid soap with effective properties in reducing theresident and transient bacteria upon the skin surface.

Example 9.Ne0mycin salt of tallow fatty acids To 5500 mls. of 5% aqueoussodium tallow soap is added 103 gms. neomycin base as a cold 5% aqueoussolution. The pH is adjusted to 8 with dilute sulfuric acid. Theprecipitate is recovered by centrifugation, washed with water and driedin a vacuum desiccator. 300 gms. of the neomycin salt of the mixedhigher fatty acids are obtained. The salt can be redissolved in excesssoap solution to provide a detergent composition possessing advantageousgermicidal properties.

Example 1 0 Following the procedure of Example 8, a mixture of equalparts of coconut oil and tallow soaps is used to prepare the neomycinsalt of the mixed fatty acids of coconut oil and tallow.

Example 11.Neomycin tallowate 17 kgs. of hydrogenated tallow fatty acidsare dissolved in a solution of 4150 gms. of 85% potassium hydroxide in75 gallons of deionized water by stirring at 70 C. After adding asolution of 5.67 kgs. of commercial grade neomycin sulfate in 5 gallonsof deionized water the mixture is cooled to 25 C. and adjusted to pH 8.0with 50% sulfuric acid. The mixture has a thick cream-like consistency.After standing overnight the product filters easily on a filter pot. Theoptical rotation of the filtrate (+0.05", 4-dm. tube) indicates thatless than 2% of the optical activity remains. The moist product weighs45.5 kgs. A Z-kg. portion is removed.

The remainder of moist filter cake is freeze-dried with a shelftemperature of F. and a pressure less than 30 microns. Drying time is 62hours. The dried product is milled, using a 28 screen. The yield aftermilling is 18.2 kgs. Assuming that the 2-kg. sample has the samemoisture content as the rest of the lot, the total yield is 19.0 kgs.The calculated yield (fatty acid plus neomycin base) is 17.0+2.69=19.69kgs. The calculated potency (neomycin base in starting material/ fattyacid neomycin base) is 137 meg/mg. Biological assays show a potency of137.3 meg/mg. The weight loss on drying is 0.59%

The neomycin tallowate is incorporated into bar soap to providecompositions with advantageous stability and germicidal activity.

What is claimed is:

1. Neomycin higher fatty acid salt wherein the fatty acid contains from12 to 18 carbon atoms, inclusive.

2. Solid neomycin higher fatty acid salt wherein the fatty acid containsfrom 12 to 18 carbon atoms, inclusive.

3. Pulverulent neomycin higher fatty acid salt wherein the fatty acidcontains from 12 to 18 carbon atoms, inelusive.

4. Dried neomycin higher fatty acid salt wherein the fatty acid containsfrom 12 to 18 carbon atoms, inclus1ve.

5. A composition of matter consisting essentially of neomycin higherfatty acid salt wherein the fatty acid contains from 12 to 18 carbonatoms, inclusive.

6. Neomycin palmitate.

7. Solid neomycin palmitate.

8. Pulverulent neomycin palmitate.

9. Dried neomycin palmitate.

10. A composition of matter consisting essentially of neomycinpalmitate.

11. Neomycin stearate.

12. Solid neomycin stearate.

13. Neomycinlaurate.

14. Pulverulent neomycin laurate.

15. Neomycin salt of mixed fatty acids wherein the fatty acids containfrom 12 to 18 carbon atoms, inclus1ve.

16. Neomycin tallowate.

17. Neomycin salt of coconut oil fatty acids.

References Cited in the file of this patent OTHER REFERENCES OKeefe:J.A.C.S., July 1949, 71 pages 2452-7. Swart: A. 8., July 1951, 73, pages3253-5

1. NEOMYCIN HIGHER FATTY ACID SALT WHEREIN THE FATTY ACID CONTAINS FROM12 TO 18 CARBON ATOMS, INCLUSIVE.